Aldose reductase is the enzyme responsible for the conversion of glucose to sorbitol in lens, sciatic nerve, retina, brain, islets of Langerhans and other tissues. Sorbitol accumulation in diabetes mellitus and galactitol accumulation in galactosemia are implicated via an osmotic effect in the formation of cataracts and neuropathy. Recently, an aldose reductase inhibitor was found to block sorbitol and glactitol formation and prevent cataracts. It is proposed to continue ongoing investigations into (1) the localization of aldose reductase in various tissues by immunological techniques, (2) study the factors leading to sorbitol accumulation in diabetic nerve, and determine the relationship of the accumulations to diabetic neuropathy using motor nerve conduction velocity measurements, (3) investigate the prevention and treatment of diabetic neuropathy by use of aldose reductase inhibitors to block sorbitol formation, (4) to study the role of the sorbitol pathway in the insulin release mechanism using collagenase isolated islets of Langerhans and the pancreas perfusion technique, and to determine the possible participation of sorbitol accumulations in the destruction of the islets of Langerhans in diabetes. BIBLIOGRAPHIC REFERENCES: Bunn, H.F., Haney, D.N., Kamin, S., Gabbay, K.H. and Gallop, P.M.: The biosynthesis of human hemoglobin A1c: Slow glycosylation of hemoglobin in vivo. J. Clin. Invest. 57:1652-1659, 1976. Gabbay, K.H., DeLuca, K., Fisher, J.N., Mako, M. and Rubenstein, A.H.: Familial proinsulinemia: A new genetic defect. NEJM 24:911-915, 1976.